Functional activation studies in health and disease often depend upon perfusion related signals to localize the source of brain activity. The goal of this proposal is to investigate perfusion related signals measured using Optical Intrinsic Signals (OIS), Near Infrared Spectroscopy (NIRS), functional Magnetic Resonance Imaging (fMRI) and Electroencephalography (EEG) during a variety of stimulus conditions. The application of different neuroimaging techniques in both animals and humans will provide a comprehensive view of the timing, distribution and capacities of these perfusion related signals and how perfusion related signals from different modalities relate. We will perform functional activation studies using OIS (multispectral and single wavelength), NIRS, fMRI, fluorescent dyes and electrical measures, to determine the relationship in space and time between these perfusion dependent, and evoked potential maps. The proposed experiments will provide a better understanding of the cascade of events collectively called the hemodynamic response. We will do this in different sensory systems of rodents and humans using a variety of stimulus and behavioral paradigms. In humans, perfusion related signals obtained using OIS and electrophysiologic methods intraoperatively will be compared with NIRS and fMRI in the same subjects. In both species, maps and the temporal profile of responses obtained from each modality will be compared within and across subjects following image registration. The proposed studies will begin with investigating the role of nitric oxide (NO) in mediating perfusion related responses. We will also characterize the nature of functional hemoglobin changes following functional activation using optical spectroscopy. Having characterized the normal characteristics of functional perfusion related responses, we will then determine how perfusion related signals are affected by various challenges (including seizure, cortical spreading depression, development, and experience- dependent plasticity). Finally, we will investigate and compare the relationship between perfusion related signals across multiple modalities. This proposal is a natural extension to our active grant where the focus was to characterize the basic temporal and spatial characteristics of optical signal responses to peripheral somesthetic stimulation. Since the coupling of brain function to cerebral perfusion provides the basis for a number of functional neuroimaging techniques, a precise knowledge of the specific underlying physiological mechanisms and their characteristics is essential. The experiments described here will help us achieve that goal.